The present invention relates to medicine and to the administration of pharmaceuticals to relieve disorders of the brain and behavior. More particularly, the present invention relates to the treatment of movement disorders, including tardive dyskinesia, tardive dystonia and tardive akathisia.
Tardive dyskinesia (TD) is an involuntary movement disorder which includes athetosis and chorea. It is usually caused by medication which blocks dopamine receptors, including many ordinary antipsychotic medications and antiemetic (antinausea) medications. Rarely is it caused by antidepressant medications. The xe2x80x9ctardivexe2x80x9d designation indicates that this disorder appears after persistent rather than acute exposure to such medication, typically at least six months in adults or three months in elderly patients. Athetosis is a slow writhing, and chorea is an undirected twitching movement. Commonly affected muscles include the tongue, the muscles around the mouth, the jaw, the neck, and the limbs, and the most visible TD movements include chewing, tongue protrusion, truncal and arm twisting, grimacing, and torticollis. TD is the most common of several tardive disorders of involuntary movement which occur in patients who take medication which blocks dopamine receptors.
Tardive dystonia tends to occur in patients who have TD, and it is characterized by long-sustained positions of muscle groups. Not only are the causes and circumstances of tardive dystonia indistinguishable from those of TD, but in medical practice the occurrence, manifestation, and treatment of tardive dystonia is not reliably distinguished from those of TD. Consequently, what refers to one refers as well to the other.
One group of medications notorious for causing TD is antipsychotic medications. Long-term use of antipsychotic medication which blocks dopamine receptors is a frequent part of the management of patients who have schizophrenia, schizoaffective disorder, psychotic mood disorders, postpartum psychosis, delusional disorder, Huntington""s Disease, agitated dementias, psychoses consequent to chronic medical conditions, borderline personality disorder, porphyria, or Tourette""s syndrome. Based on a 0.9% population prevalence for schizophrenia, 1-2% for psychotic mood disorders, 2% for agitated dementias, and 2-5% for the other conditions noted we expect that several million people in the USA have had persistent exposure to antipsychotic medications. The prevalence of TD increases with increasing exposure to such medication. Surveys report the prevalence of TD in patients with schizophrenia taking such medication as 32% after 5 years, 57% after 15 years, and 68% after 25 years (Glazer et al. 1993). In view of the increasing prevalence with greater drug exposure, the consensus among psychiatrists has long been that medication which blocks dopamine receptors is the most common cause of TD and tardive dystonia in patients they treat. Besides the duration of exposure to antipsychotic medication, advancing age increases the risk of TD (Yassa et al 1983; Hunt and Silverstone 1991); some elderly patients show persistent dyskinesia after a few weeks of an antipsychotic medication.
Antiemetic (antinausea) medications can similarly cause TD, particularly those which have antipsychotic properties or block dopamine receptors. Extended use of antidopamergic antiemetic medication can be used in the management of patients who suffer from nausea or vomiting. Nausea or vomiting can result from circumstances such as radiotherapy or chemotherapy for cancer, vertigo, pregnancy, Meniere""s disease, peptic ulcer disease, panic disorder, irritable bowel syndrome or other gastrointestinal condition, or brain tumor. Based on the common nature of these conditions we expect that several million people in the USA have had persistent exposure to antiemetic medication that blocks dopamine receptors. Risk that a medication causes TD and other movement disorders is associated with its dopamine-blocking activity, rather than the reason for its administration, whether as an antiemetic, antipsychotic, or antianxiety agent; many dopamine-blocking drugs are usable for all these effects. Patients who receive these medications for antiemetic effect experience movement disorders including TD, tardive dystonia, and tardive akathisia just as those who receive these medications for antipsychotic effect do. More rarely, tardive dyskinesia is caused by other types of medications, particularly several types of antidepressants such as amoxapine, trazodone, nefazodone, tricyclics, and serotonin-reuptake inhibitors (SSRIs). Lithium has also been reported to exacerbate or cause TD.
TD is graceless and stigmatizing, and can disable a patient psychologically as well as physically. Many TD movements resemble expressions of rudeness, and suggest loss of ability to control one""s self. These include tongue protrusion, lip puckering, facial grimacing, grunting, limb stiffening, and pelvic thrusting. These disfiguring movements are often obvious to even casual passers-by. TD can provoke repugnance, particularly in children and people with little education. This naturally leads people with TD to avoid exposure to people who are not knowledgeable friends, and to minimize their exposure to public places. This can cause substantial impairment of employability, household management, self-care, social function, and recreational function. In turn this can diminish earnings abilities, life satisfaction, and productivity, and cause unhappiness and anxiety symptoms.
In addition, long-term exposure to antipsychotic medication or dopamine-blocking antiemetic medication can produce adverse mental status changes together with or in place of TD. Analogous to the physical expressions of TD, such mental status changes are also graceless, stigmatizing, and debilitating. These mental status changes can include tardive psychosis, whose symptoms and signs are indistinguishable from schizophrenia, and other tardive psychopathology such as obsessions, compulsions, and depression (Chouinard et al 1978, Swartz 1995). Long-term exposure to dopamine-blocking medication can also produce tardive akathisia, which is a feeling of restlessness (Van Putten and Marder 1987). When akathisia is strong it is often accompanied by agitated movements, such as fidgeting, pacing, and leg-bouncing while sitting; such movements often vary considerably over the day (Sachdev and Loneragan 1993).
Akathisia differs from dyskinesia. Generally, patients do not pay attention to dyskinesia movements unless the movements are severe enough to substantially interfere with performance of a task. In contrast, akathisia generally impairs the patient""s attention, and sometimes interrupts attention and concentration. The movements of dyskinesia generally do not resemble any movements made by people who are not ill. In contrast, the movements which are sometimes made in association with akathisia are the same as made by people who are normal but worried, frustrated, or disappointed.
Physical limitations caused by TD include dysphonia (Khan et al 1994), respiratory distress (Wils 1992), dysphagia (Hayashi et al. 1997), and deformation of bearing and posture (Maeda et al 1998). Because TD is often irreversible, the difficulties, limitations, and disfigurements it produces can be permanent. Indeed, permanent movement disorders develop in animals after long-term exposure to haloperidol and other dopamine-blocking medication, e.g., in Cebus monkeys (Casey 1996).
Trials of treatment for TD to date have proven no benefit (Soares and McGrath 1999), and there are no safe and effective treatments for TD (Najib 1999; Glazer 1999). xe2x80x9cNo treatment strategy . . . is successful in most patientsxe2x80x9d (Egan et al. 1997). The only method that will generally diminish the symptoms of TD is to stop the medication that caused the TD and hope for a decrease in symptoms with time. Unfortunately, before the symptoms decrease there is often at least a temporary increase which can be difficult to endure. Additionally, the symptoms for which the patient received the medication are likely to become worse, and there are often risks of violent injury or death to the patient or others.
A method that can temporarily diminish TD in some patients is to decrease dopaminergic neurotransmission, as by increasing a dopamine-receptor blocking medication or adding a drug that depletes body levels of dopamine, such as reserpine. Although these methods tend to diminish the symptoms, they tranquilize the patient and thereby impair psychological function and mental performance; further, these medications have adverse physical side-effects such as weight gain. Moreover, while these drugs decrease the observed signs of TD in the short term they continue the pathological process that underlies the TD, and they add to it; in the long term these drugs increase TD further.
Another method that can diminish TD in some patients is to administer an xe2x80x9catypical typexe2x80x9d antipsychotic medication which does not block dopamine receptors as much, such as clozapine. Again, although this method may sometimes diminish the symptoms, it tranquilizes the patient and thereby impairs psychological function and mental performance; further, most of these medications have adverse physical side-effects. Although atypical antipsychotic medications might lessen the severity of TD in some cases, improvement is generally incomplete and new problems are exchanged for old. To illustrate, clozapine diminished TD in 43% of patients switched to it from another antipsychotic medication (Lieberman et al 1991), but clozapine""s common adverse effects include weight gain, tiredness, and suppression of white blood cell production (agranulocytosis) with lethal risk from deficient functioning of the immune system. Because of this risk of death with clozapine, blood monitoring several times per month is required. In sum, there are no generally beneficial low-risk ways to mitigate TD.
The mechanism through which dopamine-blocking medication causes TD is not established, but the high incidence of irreversible changes in TD suggests there is a permanent deterioration or unrepaired injury (Miller and Chouinard 1993). The body reacts to dopamine receptor blockade by increasing the production of the neurotransmitter dopamine within the presynaptic nerve terminal and increasing the release of dopamine from the presynaptic nerve terminal into the synaptic cleft. However, dopamine is neurotoxic, and these increased levels of dopamine that develop in reaction to dopamine-blocking agents are likely to cause neuronal deterioration. It is our studied opinion that this neurotoxicity may be diminished by blockade of L-type calcium channels, antioxidant activity, or alpha- and beta-adrenergic receptor blockade, all of which are effects of carvedilol.
Further relative to TD as the result of a neurotoxic process, some studies observe that patients with TD tend to show increased levels of excitatory neurotoxic neurotransmitters and marginally higher levels of products of protein oxidation in the central nervous system (CNS) (Tsai et al. 1998). Haloperidol induces a several-fold increase of reactive oxygen species (Sagara, 1998), which is consistent with an excitatory neurotoxic process. Such observations suggest that an oxidative process might cause or exacerbate TD, and that an antioxidant agent might protect against TD or mitigate it. On the other hand, the dopamine-receptor blocking antipsychotic drugs chlorpromazine and trifluoperazine are potent antioxidants (Dalla Libera et al. 1998), but are also notorious for frequently causing TD and other adverse conditions. Moreover, elevated reactive oxygen is associated with several medical conditions, including heart failure (Olinescu et al. 1994) and chronic renal failure (Tetta et al. 1999), without causation of tardive dyskinesia. In sum, TD is not a specific result of oxygen stress, and no specific connection between the two has been proven.
Several psychiatrists reported giving the antioxidant vitamin E to patients with TD, but most studies found no significant improvement (Barak et al 1998). Vitamin E was speculated to possibly diminish TD in a minority, but benefit beyond random variation remains an unproven assertion supported by circumstantial evidence. The MAO-inhibitor pargyline reduced acute dystonias induced by antipsychotic medication in monkeys (Heintz and Casey 1987) and might have antioxidant effects. However, other effects by pargyline include increasing body levels of catecholamines and indoleamines, which themselves affect movement disorders and have antioxidant activities (Kang et al. 1998). The attribution of antidystonia effects to antioxidant activity requires that causation by the other effects of pargyline be disproven, but they were not. Likewise, correspondence between acute dystonias in monkeys and chronic choreoathetosis of TD in humans is speculative. Nevertheless, antioxidants have not been proven to show no benefit in TD; it was our impression that trial of a specially potent antioxidant might resolve this issue and show consistent effectiveness although ordinary antioxidants have failed to do so.
Several other medications have been said to diminish TD, but their effects on TD are controversial and were small at most. These medications include lithium and valproic acid. As an example of the controversy, some observers reported that lithium exacerbates TD or causes it.
The compound carvedilol has shown exceptionally potent in vitro antioxidant activity. Some of its metabolic products are also potent antioxidants. The administration of carvedilol to three psychiatric patients hospitalized under the care of the applicant was spurred by the prominent facial disfigurement these patients showed from TD, and by the recognition of carvedilol""s antioxidant activity and its other pharmacological effects, as described below.
The absorption of carvedilol taken by mouth is typically rapid and complete. The average elimination half-life of carvedilol from the human body is about 8 hours. As with most pharmaceuticals, carvedilol is ordinarily removed from the body in a two-part process. First, the liver transforms it through one or more of the processes of hydroxylation, oxidation, sulfation, demethylation, and glucuronidation. Then, the kidneys transfer these transformed products into the urine. Some of the products of carvedilol transformation by the liver contribute to the beneficial effects of carvedilol administration. For example, the antioxidant activity of the carvedilol metabolite SB209995 has 50 to 100 times the potency of carvedilol and is 1000-fold more potent than vitamin E.
Carvedilol has several different effects on the body, including beta-1 and beta-2 adrenergic blockade, alpha-1 adrenergic blockade, antioxidant activity, L-type calcium channel blockade (Cheng et al. 1999), and inhibition of activation of stress-activated protein kinase (Yue et al 1998). All these should influence the central nervous system (CNS), excepting effects on beta-2 receptors, because they are not present in the CNS.
Among medications, carvedilol is particularly effectivexe2x80x94and apparently uniquely so among modern medicationsxe2x80x94in decreasing the mortality of patients with longstanding heart failure (Packer et al. 1996; Cleland 1998) and increasing the heart""s pump performance. The latter is measured by increasing cardiac ejection fraction (Cohn et al. 1997). Typical doses of carvedilol given to patients with congestive heart failure are 6.25 mg to 50 mg twice per day (Tenero et al. 2000). Even resistant patients, who failed to improve with the beta-blocker metoprolol, typically improved with carvedilol (Di Lenarda et al. 1999). Carvedilol""s unique action led to the suggestion of synergism of antioxidant activity and beta-adrenergic blockade (Cleland 1998), a combination that also appears unique.
However, several other effects of carvedilol have beneficial actions and probably contribute to its therapeutic effects on TD and other movement disorders. These include L-type calcium channel blockade, inhibition of protein kinase, and alpha-1-adrenergic blockade. Accordingly, we reason that the beneficial effects of carvedilol might follow actions besides beta-blockade and antioxidant activity, and that a synergism might result from a combination of effects as noted but with or without these two particular effects. We consider the compound carvedilol to have therapeutic effects in tardive movement disorders by regarding that its beneficial effects on injured unrepaired heart similarly apply also to injured unrepaired brain, whether through antioxidant activity or another action or combination of actions. We reason that, similar to its beneficial effects on the heart, carvedilol should provide beneficial effects on the brain, to promote recovery, regeneration, and improved brain function for patients with tardive movement disorders. Examples of such tardive movement disorders include adverse consequences of medications that block dopamine receptors, such as tardive dyskinesia (TD), tardive dystonia, and the agitated movements that accompany tardive akathisia.
In its usually effective doses to treat TD, the side effects of carvedilol are nearly always non-existent or mild. This is a sharp contrast with mental dulling, personality changes, impairment of psychological performance, and weight gain from the antipsychotic medications that have been used to diminish TD.
The antipsychotic medications that acutely diminish TD also acutely diminish the symptoms of several psychiatric disorders, including: 1) psychoses including schizophrenia, 2) manic episodes (mania), 3) major depressive episodes (depression), especially when the depressive episodes include psychosis, and 4) agitation in patients who have dementia. The similarity between antipsychotic medications and carvedilol in the rapid and large mitigation of TD strongly, directly, and obviously suggests that they are similar in other pharmacological effects. Pharmacologically this similarity simply and obviously suggests that carvedilol acts to diminish the effects of high levels of dopaminergic activity. Clinically this similarity simply and obviously suggests that carvedilol diminishes the signs, symptoms, and severity of 1) psychoses including schizophrenia, 2) manic episodes (mania), 3) major depressive episodes (depression), especially when the depressive episodes include psychosis, and 4) agitation in patients who have dementia.
The compound carvedilol has the chemical formula:
xc2x1-1-(carbazol-4-yloxy)-3-[[2-(o-methyoxyphenoxy)ethyl]amino]-2-propanol.
It exists in the form of optical isomers R- and S-carvedilol, and as mixtures of these isomers.
Because carvedilol""s antioxidant activity is exceptionally potent, this activity has been speculated to be responsible for carvedilol""s beneficial effects in diminishing heart failure and preventing recurrence of myocardial infarction. Carvedilol""s antioxidant activity has been w observed in several ways. It protects against injury by oxygen free radicals to endothelial cells (the inner linings of blood vessels), vascular smooth muscle, and neurons, including during ischemia and during reperfusion after ischemia. Its antioxidant activities include inhibition of several actions: 1) direct toxic effects of oxygen radicals, 2) the ability of oxygen radicals to counteract nitrogen oxide-mediated vasodilation, 3) activation by oxygen radicals of genes associated with inflammation and 4) DNA fragmentation. Carvedilol also produces increases in body levels of endogenous antioxidants such as glutathione, which indicates replenishment of antioxidant defense mechanisms.
As outlined above, carvedilol has several other actions which are beneficial to injured brain. Among these is blockade of the L-type calcium channel current (Cheng et al. 1999), an effect rarely mentioned in publications about carvedilol. Antagonists of the L-type calcium channel are neuroprotective (McLeod et al 1998). From the opposite direction, activation of the calcium channel in neuronal tissues is a critical step towards neuronal injury and degeneration (Kobayashi and Mori 1998). Accordingly, we reason that L-type calcium channel blockade by carvedilol in neuronal tissues should shield the brain from injury and degeneration, and thereby allow it to recover and regenerate from previous injury. Blockade of the L-type calcium channel is the primary effect of the pharmaceutical nimodipine, and it is reasonable to expect that carvedilol has effects similar to nimodipine. So it is relevant to note that administration of nimodipine for 12 weeks improved memory in patients who had experienced stroke, when started 1 to 2 weeks after the stroke (Sze et al. 1998). Nimodipine improved memory, performance, and mood in a 12 week trial on elderly patients with dementia (Ban et al. 1990), and it diminished essential tremor in most cases (Biary et al 1995). Similarly, L-type calcium channels contribute to dystonias in several animal models, and nimodipine mitigated these dystonias (Richter and Loscher 1996; Campbell and Hess 1999). Nimodipine provided benefit to patients with major depressive disorder and bipolar mood disorder (Pazzaglia et al. 1998; 1993). Overall, its L-type calcium channel blockade activity provides another rationale for activity by carvedilol against neuronal injury and degeneration, and for its mitigation of neuropsychiatric disorders including movement disorders.
Blockade of alpha- and beta-adrenergic receptors might contribute to carvedilol""s mitigation of tardive dyskinesia, but probably only in conjunction with carvedilol""s other effects. Only long-term and not brief duration of beta-blockade by itself diminished TD (Karniol and Portela 1982; Schrodt et al. 1982); as described below, carvedilol had an extremely rapid onset of effectiveness against TD, so this rapidity is not attributable to beta-blockade alone. In an animal model of TD, one-day and two-week trials of the beta-blocker propranolol did not diminish orofacial movements caused by the antipsychotic dopamine-receptor blocker haloperidol (Takeuchi et al 1998). Blockade of alpha-1 adrenergic receptors produces dilation of arteries and arterioles, which tends to increase blood flow and thereby dilute and carry away locally high concentrations of toxic species, such as reactive oxygen, which are produced by injured brain tissue. This should diminish toxic self-injurious xe2x80x9cpositive-feedbackxe2x80x9d cycles, as can occur with neuronal releases of calcium and glutamate. In contrast to the lack of benefit from beta-blockers alone in tardive dyskinesia, beta-blockers diminish akathisia (Sachdev and Loneragan 1993). This effect is separate from a decrease in dyskinesia, just as akathisia is separate from dyskinesia. Nevertheless, carvedilol provides a unique action to diminish both tardive dyskinesia and tardive akathisia with a single pharmaceutical agent.
None of the pharmaceutical actions of carvedilol are specific to sexual function, sexual characteristics, or gender. Accordingly, carvedilol should have similar beneficial effects in both males and females.
In the present invention, carvedilol is orally administered to decrease, prevent, or diminish the progression of the movement disorders that can be caused by medication which blocks dopamine receptors. The movement disorders include tardive dyskinesia and tardive dystonia, and they also include the agitated movements that accompany tardive akathisia. It is reasonable to expect that these particular signs and symptoms represent particular similar pathological brain states regardless of the cause of those brain states, one of which is exposure to medication which blocks dopamine receptors. The beneficial effects of carvedilol on these mental signs and symptoms and on TD should be seen in patients regardless of diagnosis or apparent causative factors. Patients for whom these symptoms or signs are a source of substantial distress or impairment should experience diminution of these symptoms and signs from a suitable dose of carvedilol, with associated decreases in symptoms, complaints, or impairments. Such mental disorders include schizophrenia, schizoaffective disorder, schizophreniform disorder, mood disorders such as major depressive disorder and bipolar disorder, obsessive-compulsive disorder, delusional disorder, anxiety disorders, psychoses consequent to chronic medical conditions, and Tourette""s syndrome.